van Kessel Emma, Berendsen Sharon, Baumfalk Anniek E, Venugopal Hema, Krijnen Eva A, Spliet Wim G M, van Hecke Wim, Giuliani Fabrizio, Seute Tatjana, van Zandvoort Martine J E, Snijders Tom J, Robe Pierre A
University Medical Center Utrecht, UMC Utrecht Brain Center, Department of Neurology & Neurosurgery, Utrecht, The Netherlands.
University Medical Center Utrecht, Department of Pathology, Utrecht, The Netherlands.
Neuro Oncol. 2022 Oct 3;24(10):1660-1670. doi: 10.1093/neuonc/noac036.
Cognitive impairment is a common and debilitating symptom in patients with diffuse glioma, and is the result of multiple factors. We hypothesized that molecular tumor characteristics influence neurocognitive functioning (NCF), and aimed to identify tumor-related markers of NCF in diffuse glioma patients.
We examined the relation between cognitive performance (executive function, memory, and psychomotor speed) and intratumoral expression levels of molecular markers in treatment-naive patients with diffuse glioma. We performed a single-center study in a consecutive cohort, through a two-step design: (1) hypothesis-free differential expression and gene set enrichment analysis to identify candidate oncogenetic markers for cognitive impairment. Nineteen molecular markers of interest were derived from this set of genes, as well as from prior knowledge; (2) correlation of cognitive performance to intratumoral expression levels of these nineteen molecular markers, measured with immunohistochemistry.
From 708 included patients with immunohistochemical data, we performed an in-depth analysis of neuropsychological data in 197, and differential expression analysis in 65 patients. After correcting for tumor volume and location, we found significant associations between expression levels of CD3 and IDH-1 and psychomotor speed; between IDH-1, ATRX, NLGN3, BDNF, CK2Beta, EAAT1, GAT-3, SRF, and memory performance; and between IDH-1, P-STAT5b, NLGN3, CK2Beta, and executive functioning. P-STAT5b, CD163, CD3, and Semaphorin-3A were independently associated after further correction for histopathological grade.
Molecular characteristics of glioma can be independent determinants of patients' cognitive functioning. This suggests that besides tumor volume, location, and histological grade, variations in glioma biology influence cognitive performance through mechanisms that include perturbation of neuronal communication. These results pave the way towards targeted cognition improving therapies in neuro-oncology.
认知障碍是弥漫性胶质瘤患者常见且使人衰弱的症状，是多种因素导致的结果。我们推测肿瘤分子特征会影响神经认知功能（NCF），并旨在识别弥漫性胶质瘤患者中与NCF相关的肿瘤标志物。
我们研究了未经治疗的弥漫性胶质瘤患者的认知表现（执行功能、记忆和精神运动速度）与肿瘤内分子标志物表达水平之间的关系。我们通过两步设计在一个连续队列中进行了单中心研究：（1）无假设差异表达和基因集富集分析，以识别认知障碍的候选致癌标志物。这组基因以及先前的知识中得出了19个感兴趣的分子标志物；（2）通过免疫组织化学测量这19个分子标志物的肿瘤内表达水平与认知表现的相关性。
在708例有免疫组织化学数据的纳入患者中，我们对197例患者的神经心理学数据进行了深入分析，并对65例患者进行了差异表达分析。校正肿瘤体积和位置后，我们发现CD3和IDH-1的表达水平与精神运动速度之间存在显著关联；IDH-1、ATRX、NLGN3、BDNF、CK2Beta、EAAT1、GAT-3、SRF与记忆表现之间存在显著关联；IDH-1、P-STAT5b、NLGN3、CK2Beta与执行功能之间存在显著关联。在进一步校正组织病理学分级后，P-STAT5b、CD163、CD3和Semaphorin-3A独立相关。
胶质瘤的分子特征可以是患者认知功能的独立决定因素。这表明除了肿瘤体积、位置和组织学分级外，胶质瘤生物学的变化还通过包括神经元通讯紊乱在内的机制影响认知表现。这些结果为神经肿瘤学中针对性的认知改善疗法铺平了道路。
